U.S. patent application number 15/918720 was filed with the patent office on 2018-07-19 for treatment of addiction and dependency.
The applicant listed for this patent is Arturo C. Taca, JR.. Invention is credited to Arturo C. Taca, JR..
Application Number | 20180200522 15/918720 |
Document ID | / |
Family ID | 58240889 |
Filed Date | 2018-07-19 |
United States Patent
Application |
20180200522 |
Kind Code |
A1 |
Taca, JR.; Arturo C. |
July 19, 2018 |
TREATMENT OF ADDICTION AND DEPENDENCY
Abstract
The present invention relates to methods of treating or
preventing addiction and relapse use of addictive agents and
treating or preventing addictive or compulsive behavior and relapse
practice of an addictive behavior or compulsion. The methods and
compositions of the invention are useful in the treatment or
prevention of addiction to any agent, including alcohol, nicotine,
marijuana, cocaine, and amphetamines, as well as compulsive and
addictive behaviors, including pathological gambling and
pathological overeating.
Inventors: |
Taca, JR.; Arturo C.; (Creve
Coeur, MO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Taca, JR.; Arturo C. |
Creve Coeur |
MO |
US |
|
|
Family ID: |
58240889 |
Appl. No.: |
15/918720 |
Filed: |
March 12, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
PCT/US2016/051367 |
Sep 12, 2016 |
|
|
|
15918720 |
|
|
|
|
62217541 |
Sep 11, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61H 2201/105 20130101;
A61N 1/36089 20130101; A61H 39/002 20130101; A61K 31/485 20130101;
A61H 2205/027 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61H 39/00 20060101 A61H039/00 |
Claims
1. A method of treating drug or alcohol abuse, addiction or
dependency comprising (a) administering to a subject in need
thereof a therapeutically effective amount of co-therapy for at
least one day comprising treatment with an auricular or
peri-auricular electro-acupuncture or neurostimulation device, (b)
co-treatment for at least one day with a composition comprising at
least one non-narcotic detoxification agent until a drug screen
tests negative and then (c) administering to a subject in need
thereof a therapeutically effective amount of an opioid
antagonist.
2. The method according to claim 1, wherein the addictive behavior
is exhibited by the subject, following exposure of the subject to
at least one stimulus, which induces in the subject an addictive
behavior.
3. The method according to claim 1, wherein the at least one
non-narcotic detoxification agent comprises at least one
sedative.
4. The method according to claim 3, wherein the at least one
sedative comprises antipsychotics, atypical antipsychotics,
alpidem, amobarbital, antihistamines, barbiturates,
benzodiazepines, chloral hydrate, chlorazepate, chlordiazepoxide,
clonazepam, clonidine, diazepam, diethyl ether, dimenhydrinate,
diphenhydramine, doxylamine, ethchlorvynol, flunitrazepam,
gamma-hydroxybutyrate, glutethimide, herbal sedatives,
imidazopyridines, kava, lorazepam, meprobamate, methaqualone,
methyl trichloride, methyprylon, olanzapine, phenabarbitol,
pentobarbital, promethazine, pyrazolopyrimidines, seroquel,
secobarbital, tiagabine, tranquilers, zaleplon, zolpidem, a
pharmaceutically acceptable salt or complex thereof, a combination
thereof, and a pharmaceutical composition comprising the same
5. The method according to claim 1, wherein the at least one day of
steps (a) and (b) is about 1 to about 7 days.
6. The method according to claim 1, wherein the opioid antagonist
comprises 7-benzylidenenaltrexone, beta-funaltrexamine,
buprenorphine, butorphanol, chlornaltrexamine, clocinnamox,
connective tissue-activating peptide, cyclazocine, diprenorphine,
ICI 154129, levallorphan, lofexidine, meptazinol, methylnaltrexone,
N,N-diallyl-tyrosyl-alpha-aminoisobutyric
acid-phenylalanyl-leucine, nalbuphine, nalmefene, nalorphine,
naloxone, naltrexone, or naltrindole, or mixtures or combinations
thereof.
7. The method according to claim 1, wherein step (c) comprises
administering to the subject a controlled release pharmaceutical
composition comprising the opioid antagonist.
8. The method according to claim 7, wherein the controlled release
pharmaceutical composition releases the opioid antagonist over a
period of more than about 4 to about 24 weeks.
9. The method according to claim 1, wherein the detoxification
agent is one or more agents selected from the group consisting of
clonidine, robaxin (muscle relaxant), pro-banthine (anti-diarrhea),
gabapentin (nerve pain and anxiety), ropinirole (restless legs),
trazodone (sleep).
10. The method according to claim 1, wherein the addiction is a
physical dependence to an addictive agent or to an addictive
behavior.
11. The method according to claim 1, wherein the auricular or
peri-auricular electro-acupuncture or neurostimulation device
comprises one or more electrodes is adapted to be placed on an ear
to transcutaneously stimulate the auricular nerve branch or
implanted in the vagus nerve.
12. The method according to claim 11, wherein the electrodes are
stimulated on the right side vagus nerve to achieve the
neurostimulation function.
13. The method according to claim 11, wherein the electrodes are
adapted to alternatively stimulate the left and right side
nerves.
14. The method according to claim 12, wherein the addictive agent
is selected from the group consisting of alcohol, caffeine,
nicotine, cannabis and cannabis derivatives, opiates and
morphine-like compounds, phencyclidine and phencyclidine-like
compounds, sedative hypnotics, psychostimulants, amphetamines and
amphetamine-related drugs, morphine, heroin, codeine, cocaine,
hydrocodone, hydromorphone, levorphanol, metapon, nalorphine,
naloxone, naltrexone, oxycodone, oxymorphone, tramadol,
ethoheptazine, fentanyl, levorphanol, meperidine, methadone,
phenazocine, propoxyphene, sufentanil, phencyclidine,
benzodiazepines, methaqualone, mecloqualone, etaqualone, pemoline,
amphetamine, methamphetamine, methylenedioxymethamphetamine,
dextroamphetamine and methylamphetamine.
15. The method according to claim 14, wherein the addictive agent
is cocaine.
16. The method according to claim 12, wherein the addictive agent
is a pain-killer or a combination of pain-killers.
17. The method according to claim 12, wherein the pain-killer is
selected from the group consisting of alfentanil, allylprodine,
alphaprodine, anileridine benzylmorphine, bezitramide,
buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,
desomorphine, dextromoramide, dezocine, diampromide,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene
fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, levallorphan, levorphanol,
levophenacylmorphan, lofenitanil, meperidine, meptazinol,
metazocine, methadone, metopon, morphine, myrophine, nalbuphine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
normorphine, norpipanone, opium, oxycodone, oxymorphone,
papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine,
phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine, propiram, propoxyphene sufentanil, tramadol and
tilidine.
18. The method according to claim 12, wherein the addictive agent
is selected from the group consisting of alfentanil, allylprodine,
alphaprodine, anileridine, apomorphine, benzylmorphine,
beta-hydroxy 3-methylfentanyl, bezitramide, carfentanil,
clonitazene, codeine, desomorphine, dextromoramide, diampromide,
dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol,
dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate,
dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,
ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine, metapon,
metazocine, methadone, methadyl acetate, metopon, morphine,
myrophine, narceine, nicomorphine, norlevorphanol, normethadone,
normorphine, norpipanone, opium, oxycodone, oxymorphone,
papaverine, phenadoxone, phenomorphan, phenoperidine, piminodine,
piritrarnide, propheptazine, promedol, properidine, propoxyphene,
remifentanil, sufentanil, thebaine, tildine and tramadol.
19. The method according to 12, wherein the addictive behavior is
selected from the group consisting of obsessive compulsive
disorder, compulsive spending and/or gambling, pathological
overeating, pathological use of electronic devices and
communication devices such as cellular phones, pathological use of
electronic video games, addiction to pornography and sex, eating
disorders such as anorexia and bulimia, kleptomania, pyromania,
compulsive over-exercising and overworking.
20. A method of treating post-acute-withdrawal syndrome (PAWS), in
a subject, wherein the method comprises administering to the
subject a therapeutically effective amount of co-therapy for at
least one day comprising (i) treatment with an auricular or
peri-auricular electro-acupuncture or neurostimulation device, and
(ii) co-treatment for at least one day with a composition
comprising at least one non-narcotic detoxification agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 62/217,541 entitled "TREATMENT OF ADDICTION
AND DEPENDENCY" filed Sep. 11, 2015, and to PCT Application No.
PCT/US16/51367 entitled "TREATMENT OF ADDICTION AND DEPENDENCY"
filed Sep. 12, 2016, both of which are hereby expressly
incorporated by reference herein to form part of the present
disclosure.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0002] The field of art disclosed herein pertains to methods of
treating or preventing addiction and relapse use of addictive
agents, and treating or preventing addictive or compulsive behavior
and relapse practice of an addictive behavior or compulsion. The
methods of the present invention make use of an electrical
stimulation device including a stimulator containing a generator
for generating electrical stimulation pulses with defined
stimulation parameters and a power supply for supplying the
generator with electrical energy, and at least one needle electrode
array for insertion into the skin surface of an area to be
stimulated.
2. Description of the Related Art
[0003] The World Health Organization (WHO) defines substance
addiction as using a substance repeatedly, despite knowing and
experiencing harmful effects. Substance addiction is a chronic,
relapsing disease characterized by a loss of control over drug use,
compulsive drug seeking and craving for a substance, use that
persists despite negative consequences, and physical and/or
psychological dependence on the substance. Substance addiction
typically follows a course of tolerance, withdrawal, compulsive
drug taking behavior, drug seeking behavior, and relapse. Substance
abuse and addiction are public health issues with significant
social and economic impact on both the addict and society by
playing a major role in violent crime and the spread of infectious
diseases. Addictive substances include alcohol, caffeine, nicotine,
cannabis (marijuana) and cannabis derivatives, opiates and other
morphine-like opioid agonists such as heroin, phencyclidine and
phencyclidine-like compounds, sedative ipnotics such as
benzodiazepines and barbiturates and psychostimulants such as
cocaine, amphetamines and amphetamine-related drugs such as
dextroamphetamine and methylamphetamine.
[0004] According to the WHO, an estimated 13 million people abuse
opiates worldwide, including 9 million heroin addicts. More than
25% of opiate abusers die from suicide, homicide, or an infectious
disease, such as HIV and hepatitis, within 10-20 years of becoming
addicted. Tolerance and physical dependence can develop within two
to three days. While abuse and addiction to opioid agents is a
known phenomenon, what is new is the worsening of this problem in
the recent years (Compton and Volkow 2006; Compton and Volkow
2006). Epidemiological surveys of youth in the United States in
2003 indicated that opioid analgesics were among the most
frequently abused illicit drugs among secondary students (12th
graders), second only to marijuana (Delva et al. 2005).
Furthermore, the past few years have seen a marked increase in the
use of opioid medications in the United States and an even greater
increase in problems associated with such use. This upsurge in use
and problems is particularly concerning because it seems to
represent an expanded pathway to opioid addiction (Siegal, Carlson
et al. 2003). According to recent epidemiological data, 4.7% (i.e.,
11.0 million) United States household residents over the age of
twelve abused an opioid medication in 2002 and 13.7% of these
persons (i.e., 1.5 million) endorsed the symptoms of a DSM-IV
opioid use disorder (Association 1994; Substance Abuse and Mental
Health Services Administration 2004). As recently reviewed by
Compton and Volkow, the annual incidence of opioid analgesic abuse
increased from 628,000 initiates in 1990 to 2.4 million initiates
in 2001 (Administration 2003; Substance Abuse and Mental Health
Services Administration 2003).
[0005] The goals for treatment of opiate addiction, as with other
types of substance addictions, are to discontinue the use of the
opiate while minimizing painful withdrawal symptoms and preventing
relapse. Current treatments involve replacing the addictive drug
with a substitution of an opioid receptor agonist or mixed
agonist/antagonist. An alternative approach consists of the use of
an opioid receptor antagonist to block the effect of the agonist.
Antagonists provide no relief from pain or other withdrawal
symptoms; rather, they can precipitate withdrawal, and their
therapeutic use was associated with increased accidental opioid
agonists overdosing and increased lethality. Use of agonists with a
lower affinity for the receptors results in the least severe
withdrawal symptoms, but it can lead to a dependence on the
substitute opiate. Also, many substitution therapies take 3-6
months, allowing time for addicts to stop treatment midway.
[0006] The use of electrical stimulation for treatment of medical
conditions has been well known in the art for nearly two thousand
years. It has been recognized that electrical stimulation of the
brain and/or the peripheral nervous system and/or direct
stimulation of the malfunctioning tissue, which stimulation is
generally a wholly reversible and non-destructive treatment, holds
significant promise for the treatment of many ailments.
[0007] Neural stimulation has been the subject of a number of
studies and has been proposed for several therapies. The autonomic
system controls physiological activities of the body and the
imbalance of autonomic tone is related to many diseases and
conditions. Reduced autonomic balance (increase in sympathetic and
decrease in parasympathetic cardiac tone) during heart failure has
been shown to be associated with left ventricular dysfunction and
increased mortality. Sympathetic inhibition, as well as
parasympathetic activation, has been associated with reduced
arrhythmia vulnerability following a myocardial infarction. Vagus
nerve stimulation has been proposed to treat sleep disorders,
gastrointestinal motility, eating disorders, obesity, anorexia,
gastrointestinal tract disorders, hypertension, coma, and
epilepsy.
[0008] Neural stimulation targeting other nerves has shown similar
beneficial effect. Improved systems and methods for stimulating
neural targets are needed. The present invention relates to methods
of treatment for addiction using a device for the punctual
stimulation of endings of nerves which are located in the region of
the ears and run to the brainstem nuclei, said device having a
battery-powered therapeutic current generator which is provided
with an electronic circuit forming a low-frequency therapeutic
current, and which device further has at least one stimulation
needle electrode to be positioned at a nerve ending.
[0009] Aspects of the present disclosure are directed toward
auricular nerve stimulation at terminals in one and/or both ear
lobes, and based on events that are simultaneous, synchronous, in
alternating sequences and/or with different off times, and to
providing systems, apparatuses, and methods for application of
stimulation for reproducible stimulation of the auricular nerve or
nerves.
[0010] Aspects of the present disclosure are directed toward
auricular nerve stimulation at terminals in one and/or both ear
lobes, and based on events that are simultaneous, synchronous, in
alternating sequences and/or with different off times, and to
providing systems, apparatuses, and methods for application of
stimulation for reproducible stimulation of the auricular nerve or
nerves with minimal operator dependence.
[0011] Device, systems, methods and kits can be useful for
auricular stimulation. One such device relates to auricular
stimulation. The device includes one or two earpieces having an
electrode arrangement configured and arranged to deliver a series
of electrical stimulation signals to one or two auricular
locations. One or two pulse-generator circuits is/are configured
and arranged to generate the series of electrical stimulation
signals having a stimulation profile, and deliver the electrical
stimulation signals to the electrode arrangement. A sensor is
configured and arranged to generate a feedback signal that is
responsive to the electrical stimulation signals. A feedback
circuit is configured and arranged to modify the stimulation
profile in response to the feedback signal.
[0012] Device, systems, methods and kits that can be useful for
auricular stimulation are generally known in the art. See, for
example, U.S. Pat. Nos. 9,415,220; 9,061,148; 8,942,814; 8,731,672;
8,175,699; 8,010,197; 7,781,486; 7,725,188; 7,711,430; 7,660,637;
7,336,993; 7,200,444; 5,324,287.
[0013] Clearly, there is a need in the art for new methods for
treating and preventing addiction and the relapse use of addictive
agents. The present invention meets these needs by providing
methods and pharmaceutical combinations useful in treating and
preventing addiction and recidivism.
[0014] Certain embodiments of the present disclosure are directed
towards methods of treatment using an auricular stimulation device
that has an earpiece having an electrode and configured and
arranged to deliver a series of electrical stimulation signals to a
first auricular location of a particular individual based upon
anatomical measurements from the particular individual. A
pulse-generator circuit is configured and arranged to generate the
series of electrical stimulation signals, and to deliver the
electrical stimulation signals to the electrode.
[0015] The present invention provides for a system and methods not
based upon acupuncture technique or "points" but rather peripheral
nerve field stimulation, anatomical location of cranial nerves,
peripheral nerves, arterial branches and/or neurovascular bundles,
and energy transfer based upon accepted laws of energy transfer in
human tissue. These physical entities can be selectively targeted
by percutaneous implantation of one or more electrode-needle
complex either with a single needle or an array connected to a
generator set at a selected frequency or modulating frequency
range.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The various exemplary embodiments of the present invention,
which will become more apparent as the description proceeds, are
described in the following detailed description in conjunction with
the accompanying drawings, in which:
[0017] FIG. 1A is a side view of a head of a human being with an
electrical stimulation device in an auricular application,
according to one embodiment;
[0018] FIG. 1B is a block diagram of the electrical stimulation
device of FIG. 1B, according to one embodiment;
DETAILED DESCRIPTION
[0019] The present invention relates to the use of one or more
non-narcotic detox medications used in combination with one or more
auricular or peri-auricular electro-acupuncture or neurostimulation
(e.g., a BRIDGE) device for the treatment and prevention of
addictions and relapse to addictive use or behavior. Accordingly,
the present invention provides methods and related compositions,
unit dosage forms, and kits useful for the treatment and prevention
of addictions, and for the treatment and prevention of relapse use
of addictive agents or practice of addictive or compulsive
behaviors.
[0020] In one embodiment, the present invention includes a method
of treating or preventing an addiction, comprising determining that
a subject has or is at risk of developing an addiction, and
providing to the subject one or more non-narcotic detox medications
used in combination with one or more auricular or peri-auricular
electro-acupuncture or neurostimulation (e.g., a BRIDGE) device for
a time effective for the treatment or prevention of the
addiction.
[0021] In a related embodiment, the present invention provides a
method of treating or preventing an addiction, comprising providing
to a subject having an addiction one or more non-narcotic detox
medications used in combination with one or more auricular or
peri-auricular electro-acupuncture or neurostimulation (e.g., a
BRIDGE) device and an additional therapeutic agent, wherein each of
the one or more non-narcotic detox medications and the additional
therapeutic agent contribute to the effective treatment or
prevention of the addiction.
[0022] In one or more embodiments, the present invention provides
for methods of treating drug or alcohol abuse, addiction or
dependency in a subject, wherein the method comprises (a)
administering to the subject a therapeutically effective amount of
co-therapy for at least one day comprising treatment with an
auricular or peri-auricular electro-acupuncture or neurostimulation
device, (b) co-treatment for at least one day with the composition
until a drug screen tests negative and then (c) administering to
the subject a therapeutically effective amount of an opioid
antagonist.
[0023] In one or more embodiments, the present invention provides
for methods of treating drug or alcohol abuse, addiction or
dependency comprising (a) administering to a subject in need
thereof a therapeutically effective amount of co-therapy for at
least one day comprising treatment with an auricular or
peri-auricular electro-acupuncture or neurostimulation device, (b)
co-treatment for at least one day with a composition comprising at
least one non-narcotic detoxification agent and then (c)
administering to a subject in need thereof a therapeutically
effective amount of an opioid antagonist.
[0024] In one embodiment, the present invention provides for a
composition comprising at least one non-narcotic detoxification
agent for use in a method of treating drug or alcohol abuse,
addiction or dependency in a subject, wherein the method comprises
(a) administering to the subject a therapeutically effective amount
of co-therapy for at least one day comprising treatment with an
auricular or peri-auricular electro-acupuncture or neurostimulation
device, (b) co-treatment for at least one day with the composition
until a drug screen tests negative and then (c) administering to
the subject a therapeutically effective amount of an opioid
antagonist.
[0025] In one or more embodiments, the present invention provides
for methods of treating post-acute-withdrawal syndrome (PAWS), in a
subject in need, wherein the method comprises administering to the
subject a therapeutically effective amount of co-therapy for at
least one day comprising (i) treatment with an auricular or
peri-auricular electro-acupuncture or neurostimulation device, and
(ii) co-treatment for at least one day with a composition
comprising at least one non-narcotic detoxification agent.
[0026] In one or more embodiments, the present invention provides
for methods of treating post-acute-withdrawal syndrome (PAWS), in a
subject, wherein the method comprises (a) administering to the
subject a therapeutically effective amount of co-therapy for at
least one day comprising (i) treatment with an auricular or
peri-auricular electro-acupuncture or neurostimulation device, and
(ii) co-treatment for at least one day with a composition
comprising at least one non-narcotic detoxification agent until
symptoms subside and then (b) administering to the subject a
therapeutically effective amount of an opioid antagonist.
[0027] In one or more embodiments, the present invention provides
for methods of treating post-acute-withdrawal syndrome (PAWS),
comprising (a) administering to a subject in need thereof a
therapeutically effective amount of co-therapy for at least one day
comprising treatment with an auricular or peri-auricular
electro-acupuncture or neurostimulation device, (b) co-treatment
for at least one day with a composition comprising at least one
non-narcotic detoxification agent until sufficient reduction of
symptoms and then (c) administering to a subject in need thereof a
therapeutically effective amount of at least one non-narcotic
detoxification agent.
[0028] In one embodiment, the present invention provides for a
composition comprising at least one non-narcotic detoxification
agent for use in a method of treating post-acute-withdrawal
syndrome (PAWS), in a subject, wherein the method comprises (a)
administering to the subject a therapeutically effective amount of
co-therapy for at least one day comprising treatment with an
auricular or peri-auricular electro-acupuncture or neurostimulation
device, (b) co-treatment for at least one day with the composition
and then (c) administering to the subject a therapeutically
effective amount of an opioid antagonist.
[0029] Withdrawal syndrome is a cluster of symptoms that occur for
1-2 weeks when a person stops taking an addictive or prescription
drug. Some people take medications and do not become addicted to
them but still experience withdrawal if they suddenly stop taking
these medicines. Although withdrawal symptoms are uncomfortable,
they typically end after two weeks at most, especially when a
medical professional oversees the detox process. However, some
drugs can lead to prolonged or protracted withdrawal, lasting for
months and sometimes up to a year. People who consume a large
amount of an intoxicating substance for a long time are more likely
to develop this condition, which is called post-acute withdrawal
syndrome (PAWS). It may take up to two years before neurochemistry
returns to something resembling a normal state. After the acute
stage of withdrawal ends, the post-acute stage begins, with an
array of troubling symptoms. This period can last for 20 months or
longer.
[0030] Post-acute-withdrawal syndrome (PAWS), or the terms
post-withdrawal syndrome, protracted withdrawal syndrome, prolonged
withdrawal syndromes describe a set of persistent impairments that
occur after withdrawal from alcohol, opiates, benzodiazepines,
antidepressants and other substances. Symptoms of PAWS are
individual to each drug, but there are some common symptoms,
including: Hostility or aggression; Anxiety, panic, or fear;
Irritability and mood swings; Depression; Exhaustion or fatigue;
and Inability to sleep. Other symptoms include: Psychosocial
dysfunction, Anhedonia, Impaired interpersonal skills,
Obsessive-compulsive behavior, Feelings of guilt, Autonomic
disturbances, Pessimistic thoughts, Impaired concentration, Lack of
initiative, Craving, Inability to think clearly, Memory problems,
Emotional overreactions or numbness, Physical coordination
problems, Stress sensitivity, Increased sensitivity to pain, Dreams
of using substance.
[0031] In PAWS treatments, at least one non-narcotic detoxification
agent may comprise one or more of buprenorphine (Suboxone),
methadone, naltrexone, acamprosate, flumazenil and combinations
thereof.
[0032] The syndrome may be in part due to persisting physiological
adaptations in the central nervous system manifested in the form of
continuing but slowly reversible tolerance, disturbances in
neurotransmitters and resultant hyperexcitability of neuronal
pathways.
[0033] The same neuronal pathways that are dysfunctional that cause
the syndrome of PAWS are thoughts to be the targets of affect
during peripheral nerve field stimulation. These pathways are
stimulated using the similar neuroanatomy pathways that are
identified during the treatment of opiate withdrawal namely: the
autonomical nervous system, the neocortex the limbic system
structures of the deep brain, the amygdala, and the spine.
[0034] Peripheral nerve field stimulators are safe and effective
tools to rapidly reduce the signs and symptoms associated of
Post-Acute Withdrawal Syndrome (PAWS).
[0035] In one embodiment, the detoxification agent (anti-addiction
agent) is a therapeutically effective amount of one or more opioid
antagonist. In one embodiment, the detoxification agent is an
opioid agonist, an opioid antagonist, or combinations thereof. In
one embodiment, the detoxification agent is a therapeutically
effective amount of an opioid agonist and an opioid antagonist.
[0036] In one embodiment, the detoxification agent is one or more
agents selected from the group consisting of naltrexone,
methylnaltrexone, nalmefene, nalmephene, disulfuram, acamprosate,
topiramate, risperidone, paliperidone, ondansetron, fluoxetine,
sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine and
duloxetine.
[0037] In certain embodiments, naltrexone is used in combination
therapy with one or more other agents for treating an addiction.
Such agents include, but are not limited to, analgesics, NSAIDs,
antiemetics, antidiarrheals, alpha-2-antagonists, benzodiazepines,
anticonvulsants, antidepressants, and insomnia therapeutics.
Exemplary agents include, but are not limited to, buprenorphine,
naloxone, methadone, levomethadyl acetate, L-alpha acetylmethadol
(LAAM), hydroxyzine, diphenoxylate, atropine, chlordiazepoxide,
carbamazepine, mianserin, benzodiazepine, phenoziazine, disulfuram,
acamprosate, topiramate, ondansetron, sertraline, bupropion,
amantadine, amiloride, isradipine, tiagabine, baclofen,
propranolol, desipramine, carbamazepine, valproate, lamotrigine,
doxepin, fluoxetine, imipramine, moclobemide, nortriptyline,
paroxetine, sertraline, tryptophan, venlafaxine, trazodone,
quetiapine, zolpidem, zopiclone, zaleplon, gabapentin, naltrexone,
paracetamol, metoclopramide, loperamide, clonidine, lofexidine, and
diazepam.
[0038] In one embodiment, the detoxification agent is one or more
agents selected from the group consisting of Clonidine,
methocarbamol (Robaxin), pro-banthine, gabapentin, ropinirole, and
trazodone.
[0039] In certain embodiments in which a subject is provided with
both an opioid antagonist and an opioid agonist, the opioid agonist
is selected from the group consisting of alfentanil, allylprodine,
alphaprodine, anileridine, apomorphine, benzylmorphine,
beta-hydroxy 3-methylfentanyl, bezitramide, carfentanil,
clonitazene, codeine, desomorphine, dextromoramide,
diacetylmorphine (heroin), diampromide, dihydrocodeine,
dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan,
lofentanil, meperidine, metapon, metazocine, methadone, methadyl
acetate, metopon, morphine, myrophine, narceine, nicomorphine,
norlevorphanol, normethadone, normorphine, norpipanone, opium,
oxycodone, oxymorphone, papaverine, phenadoxone, phenomorphan,
phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine, propoxyphene, remifentanil, sufentanil, thebaine,
tildine, tramadol, and any combination thereof.
[0040] In certain embodiments, naltrexone is used in combination
therapy with one or more other anti-epileptic agents selected from
the group consisting of carbamazepine (Tegretol), divalproex sodium
(Depakote), felbamate (Felbatol), gabapentin (Neurontin),
lamotrigine (Lamictal), oxcarbazepine (Trileptal), phenytoin
(Dilantin), topiramate (Topamax), and zonisamide (Zonegran)
[0041] In certain embodiments, naltrexone is used in combination
therapy with one or more other anti-migraine agents selected from
the group consisting of serotonin 5HT1d receptor agonists,
almotriptan (Axert), frovatriptan (Frova), naratriptan (Amerge),
rizatriptan (Rizalt), sumatriptan (Imitrex), zolmitriptan (Zomig),
ergot alkaloids dihydroergotamine (DHE),
isometheptine/dichlorophenazone (Midrin), caffeine and pizotifen
(Sanomigran)
[0042] In certain embodiments, naltrexone is used in combination
therapy with one or more other sedative-hypnotic agents selected
from the group consisting of benzodiazepines, alprazolam (Xanax),
clonazepam (Klonopin), clorazepate (Tranxene), diazepam (Valium),
flumazenil (Romazicon), antagonist lorazepam (Ativan), midazolam
(Versed), triazolam (Halcion), barbiturates/Anesthetics
pentobarbital (Nembutal), phenobarbital (Luminal), thiopental
(Pentothal), non-depressant anxiolytic and buspirone (BuSpar)
[0043] In certain embodiments, naltrexone is used in combination
therapy with one or more other pain management agents selected from
the group consisting of beta-endorphin, dynorphin, enkephalins,
codeine, etorphine, fentanyl (Sublimaze), hydrocodeine,
hydromorphone, meperidine (Demerol), methadone (Dolophine),
morphine, oxycodone, propoxyphene, buprenorphine, dezocine
(Dalgan), nalbuphine (Nubain), pentazocine (Talwain), naloxone
(Narcan), acetaminophen (tylenol), and tramadol (ultram)
[0044] In certain embodiments, naltrexone is used in combination
therapy with one or more other anti-Parkinsonism agents selected
from the group consisting of levodopa, carbidopa, bromocriptine
(Parlodel), pergolide (Permax), amantadine (Symmetrel), selegiline
(Deprenyl), anticholinergic agents, dopamine Agonists, pramipexole
(Mirapex), ropinirole (Requip), COMT inhibitors, entacapone
(Comtan) and tolcapone (Tasmar).
[0045] In certain embodiments, naltrexone is used in combination
therapy with one or more other anti-spasticity agents selected from
the group consisting of baclofen, (Lioresal), botulinum toxin type
A (Botox), carisoprodol (Soma, Rela), chlorphenesin (Maolate),
chlorzoxazone (Paraflex), cyclobenzaprine (Flexeril), dantrolene
(Dantrium), diazepam (Valium), metaxalone (Skelaxin), methocarbamol
(Robaxin), orphenadrine (Norflex), and tizanidine (Zanaflex).
[0046] In certain embodiments of the methods of the present
invention, the subject is addicted to an addictive agent, or at
risk for relapse use of an addictive agent. In particular
embodiments, the addictive agent is alcohol, nicotine, marijuana, a
marijuana derivative, an opioid agonist, a benzodiazepine, a
barbiturate, or a psychostimulant. In certain embodiments, the
opioid agonist is selected from the group consisting of: morphine,
methadone, fentanyl, sufentanil and heroin. In certain embodiments,
the psychostimulant is cocaine, amphetamine or an. amphetamine
derivative. In addition, the subject may be addicted to more than
one addictive agent, and the pharmaceutical compositions, unit
dosage forms, and kits may be useful for treating or preventing
addiction or relapse use of more than one addictive agent.
[0047] In a related embodiment, the present invention provides a
method of treating or preventing an addiction, comprising providing
to a subject having an addiction a peroxisome
proliferator-activated receptor gamma (PPAR-gamma agonist) and an
additional therapeutic agent, wherein each of the PPAR-gamma
agonist and the additional therapeutic agent contribute to the
effective treatment or prevention of the addiction. In certain
embodiments of the methods of treating or preventing addiction of
the present invention, the PPAR-gamma agonist is a
thiazolidinedione (TZD). In particular embodiments, the TZD is
pioglitazone, rosiglitazone, ciglitazone, troglitazone,
englitazone, rivoglitazone, or darglidazone. In certain
embodiments, the additional therapeutic agent is an opioid
antagonist, a mixed opioid partial agonist/antagonist, an
antidepressant, an antiepileptic, an antiemetic, a
corticotrophin-releasing factor-1 (CRF-1) receptor antagonist, a
selective serotonin-3 (5-HT3) antagonist, a 5-HT.sub.2A/2C
antagonist, or a cannabinoid-1 (CB1) receptor antagonist. In
particular embodiments, the opioid antagonist is naltrexone or
nalmefene. In particular embodiments, the antidepressant is
fluoxetine, mirtazapine, or bupropion. In particular embodiments,
the antiepileptic is topiramate, levetiracetam, or gabapentin. In
one embodiment, the CRF-1 receptor antagonist is antalarmin. In
another embodiment, the selective serotonin-3 (5-HT3) antagonist is
ondansetron. In particular embodiments, the cannabinoid-1 (CB1)
receptor antagonist is rimonabant or tanarabant. In one embodiment,
the mixed opioid agonist/antagonist is buprenorphine.
[0048] In other embodiments of the present invention, the subject
is addicted to an addictive or compulsive behavior or at risk for
relapse practice of an addictive or compulsive behavior. In
particular embodiments, the addictive or compulsive behavior is
pathological gambling, pathological overeating, pathological use of
electronic devices, pathological use of electronic video games,
pathological use of electronic communication devices, pathological
use of cellular telephones, addiction to pornography, sex
addiction, obsessive compulsive disorder, compulsive spending,
anorexia, bulimia, intermittent explosive disorder, kleptomania,
pyromania, trichotillomania, compulsive overexercising, and
compulsive overworking. In addition, the subject may be addicted to
more than one addictive or compulsive behavior, and the
pharmaceutical compositions, unit dosage forms, and kits may be
useful for treating or preventing addiction or relapse use of more
than one addictive or compulsive behavior.
[0049] In particular embodiments of any of the methods of the
present invention, the addictive agent is alcohol and the
additional therapeutic agent is an opioid antagonist or a mixed
opioid antagonist/partial agonist in one embodiment, the opioid
antagonist is naltrexone. In another embodiment, the mixed opioid
partial agonist/antagonist is buprenorphine.
[0050] In other particular embodiments of any of the methods of the
present. invention, the addictive agent is nicotine and the
additional therapeutic agent is an antidepressant. In one
embodiment, the antidepressant is bupropion.
[0051] In further particular embodiments of any of the methods of
the present invention, the addictive agent is a psychostimulant and
the additional therapeutic agent is an antidepressant. In one
embodiment, the antidepressant is bupropion.
[0052] In certain embodiments of pharmaceutical compositions of the
present invention comprises one or more additional therapeutic. In
certain embodiments the one or more additional therapeutic agent is
an opioid antagonist, a mixed opioid partial agonistlantagonist, an
antidepressant, an antiepileptic, an antiemetic,
corticotrophin-releasing factor-1 (CRF-1) receptor antagonist, a
selective serotonin-3 (5-HT3) antagonist, a 5-HT2A/2C antagonist,
and a cannabinoid-1 (CB1) receptor antagonist. In one embodiment,
the opioid antagonist is naltrexone or nalmefene. In one
embodiment, the antidepressant is fluoxetine, mirtazapine, or
bupropion. In one embodiment, the antiepileptic is selected from
the group consisting of: topiramate, levetiracetam, and gabapentin.
In one embodiment, the CRF-1 receptor antagonist is antalarmin. In
one embodiment, the selective serotonin-3 (5-HT3) antagonist is
ondansetron. In one embodiment, the cannabinoid-1 (CB1) receptor
antagonist is rimonabant or tanarabant. In one embodiment, the
mixed opioid agonist/antagonist is buprenorphine.
[0053] An opioid antagonist acts on one or more opioid receptors.
At least three types of opioid receptors, mu, kappa, and delta
opioid receptors, have been reported, and opioid antagonists are
generally classified by their effects on the opioid receptors.
Opioid antagonists may antagonize central receptors, peripheral
receptors or both. Naloxone and naltrexone are commonly used opioid
antagonist drugs that are competitive that bind to the opioid
receptors with higher affinity than agonists, but that do not
activate the receptors. This effectively blocks the receptor,
preventing the body from responding to opiates and endorphins.
[0054] Many opioid antagonists are not pure antagonists but also
produce some weak opioid partial agonist effects and can produce
analgesic effects when administered in high doses to opioid-naive
individuals. Examples of such compounds include nalorphine, and
levallorphan. However, the analgesic effects from these drugs are
limited and tend to be accompanied by dysphoria, most likely due to
action at the kappa opioid receptor. Since they induce opioid
withdrawal effects in people who are taking, or have previously
used, opioid full agonists, these drugs are considered to be
antagonists.
[0055] Naloxone is one example of an opioid antagonist that has no
partial agonist effects. Instead, it is a weak inverse agonist at
mu opioid receptors and is used for treating opioid overdose.
[0056] Specific examples of opioid antagonists that may be used
according to the invention include alvimopan, binaltorphimine,
buprenorphine, cyclazocine, cyclorphan, cypridime, dinicotinate,
beta-funaltrexamine, levallorphan, methylnaltrexone, nalbuphine,
nalide, nalmefene, nalmexone, nalorphine, nalorphine dinicotinate,
naloxone, naloxonazine, naltrendol, naltrexone, naltrindole,
oxilorphan, and pentazocine.
[0057] The term addiction is used to describe a recurring
compulsion by an individual to engage in some specific activity,
despite harmful consequences to the individual's health, mental
state or social life. The term is often reserved for drug
addictions, but it is sometimes applied to other compulsions, such
as problem gambling, and compulsive overeating. Factors that have
been suggested as causes of addiction include genetic,
biological/pharmacological and social factors. The medical
community now makes a careful theoretical distinction between
physical or physiological dependence (characterized by symptoms of
withdrawal) and psychological dependence (sometimes referred to
simply as addiction). Addiction is now narrowly defined as
"uncontrolled, compulsive use." If there is no harm being suffered
by, or damage done to, the patient or another party, then
clinically it may be considered compulsive, but to the definition
of some it is not categorized as "addiction". In practice, the two
kinds of addiction (physiological dependence and psychological
dependence) are not always easy to distinguish. Addictions often
have both physical and psychological components. Physical
dependence (or drug dependence) refers to a state resulting from
habitual use of a drug, where negative physical withdrawal symptoms
result from abrupt discontinuation. Examples of addictive agents
for which a user may develop a physical dependence include
nicotine, opioids, barbiturates, benzodiazepines, alcohol, i.e.,
ethyl alcohol, GHB, and methaqualone.
[0058] Physical dependence (or drug dependence) refers to a state
resulting from habitual use of a drug, where negative physical
withdrawal symptoms result from abrupt discontinuation. Examples of
addictive agents for which a user may develop a physical dependence
include nicotine, opioids, barbiturates, benzodiazepines, alcohol,
i.e., ethyl alcohol, GHB, and methaqualone.
[0059] Commonly abused stimulants such as cocaine or amphetamine
class drugs are not believed to cause significant physical
dependence. However, their potential for extreme physiological
addiction can compel the user to consume amounts which become
physically damaging, but life-threatening withdrawal effects have
not been observed.
[0060] As used herein, addictive agents includes any and all agents
to which a subject can become addicted, either physically or
psychologically, or both. As noted above, addiction includes
addiction to chemical entities, such as drugs, e.g., ethyl alcohol,
nicotine, or cocaine, as well as addiction to other behaviors,
e.g., pathological gambling, pathological overeating, pathological
use of electronic devices, e.g., BlackBerry, pathological use of
electronic video games, pathological use of electronic
communication devices, pathological use of cellular telephones,
addiction to pornography, sex addiction, obsessive compulsive
disorder, compulsive spending, anorexia, bulimia, intermittent
explosive disorder, kleptomania, pyromania, trichotillomania,
compulsive overexercising, and compulsive overworking.
[0061] Addictive agents include addictive recreational drugs, as
well as addictive medications. Examples of addictive agents
include, but are not limited to, alcohol, e.g., ethyl alcohol,
gamma hydroxybutyrate (GHB), caffeine, nicotine, cannabis
(marijuana) and cannabis derivatives, opiates and other
morphine-like opioid agonists such as heroin, phencyclidine and
phencyclidine-like compounds, sedative ipnotics such as
benzodiazepines, methaqualone, mecloqualone, etaqualone and
barbiturates and psychostimulants such as cocaine, amphetamines and
amphetamine-related drugs such as dextroamphetamine and
methylamphetamine. Other examples include LSD, psilocybin, extasy
and other hallucinogens. Examples of addictive medications include,
e.g., benzodiazepines, barbiturates, and pain medications including
alfentanil, allylprodine, alphaprodine, anileridine benzylmorphine,
bezitramide, buprenorphine, butorphanol, clonitazene, codeine,
cyclazocine, desomorphine, dextromoramide, dezocine, diampromide,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene
fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, levallorphan, levorphanol,
levophenacylmorphan, lofenitanil, meperidine, meptazinol,
metazocine, methadone, metopon, morphine, myrophine, nalbuphine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
normorphine, norpipanone, opium, oxycodone, oxycontin, oxymorphone,
papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine,
phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine, propiram, propoxyphene sufentanil, tramadol, tilidine,
salts thereof, mixtures of any of the foregoing, mixed
.mu.-agonists/antagonists, and the like.
[0062] In certain embodiments, a subject may be addicted to an
opioid agonist. The terms "opioid agonist," "opioid" and "opiate"
are used interchangably herein and are used to designate a group of
drugs that are, to varying degrees, opium- or morphine-like in
their properties. Their main use is for pain relief. These agents
work by binding to opioid receptors, which are found principally in
the central nervous system and the gastrointestinal tract. Opiates
are also addictive agents. Opiates include, e.g., alfentanil,
allylprodine, alphaprodine, anileridine, apomorphine,
benzylmorphine, beta-hydroxy 3-methfentanyl, bezitramide,
carfentanil, clonitazene, codeine, desomorphine, dextromoramide,
diacetylmorphine (heroin), diampromide, dihydrocodeine,
dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine,
ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,
etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan,
lofentanil, meperidine, metapore, metazocine, methadone, methadyl
acetate, metopon, morphine, myrophine, narceine, nicomorphine,
norlevorphanol, normethadone, normorphine, norpipanone, opium,
oxycodone, oxymorphone, papaverine, phenadoxone, phenomorphan,
phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine, propoxyphene, remifentanil, sufentanil, thebaine,
tildine, and tramadol. Naturally occurring opiates include, e.g.,
codeine, morphine, noscapine, papaverine, and thebaine.
Semi-synthetic opioids include, e.g., diacetylmorphine,
hydrocodone, hydromorphone, levorphanol, metapon, nalorphine,
naloxone, naltrexone, oxycodone, oxyrnorphone, and tramadol.
Synthetic opioids include, e.g., ethoheptazine, fentanyl,
levorphanol, meperidine, methadone, phenazocine, propoxyphene and
sufentanil. Three broad classifications of opiates are
phenanthrenes, phenylheptylamines, and phenylpiperidines. Examples
of phenanthrenes include codeine, etorpine, hydrocodone,
hydromorphone, morphine, oxycodone, and oxymorphone. Examples of
phenylheptylamines include dimeheptanol, dimenoxadol, dipipanone,
isomethadone, methadone, methadyl acetate, and propoxyphene.
Examples of phenylpiperidines include alfentanyl, alphaprodine,
beta-promedol, carfentanyl, fentanyl, lofentanil, meperidine,
properidine, and sufentanil,
[0063] The present invention provides for systems and methods for
reducing or eliminating the physical signs and symptoms of
withdrawal from addiction or substance abuse e.g., opiates,
narcotics, alcohol, amphetamines, methamphetamines or any substance
that: is known to cause withdrawal symptoms.
[0064] Reducing the subjective and objective scores of C.O.W.S. or
any other outcomes or assessment tool with any auricular or
peri-auricular electro-acupuncture or neurostimulation device, with
the intention of stabilizing the patient to a point that any drug
or alcohol screen can be found "negative" (clean), with the
intention of getting the patient to a medication like
naltrexon/naloxone (Vivitrol) or any other similar medication.
[0065] The use of medication assisted detoxification along with the
BRIDGE device or any similar device to provide humane
detoxification to avoid addicting medications.
[0066] That this protocol will reduce the normal withdrawal times
from 10-21 days, to 2-11 days.
[0067] That this protocol offers the first ever opportunity for a
patient to choose a treatment that will allow them to get off of
addicting medications, alcohol, heroin or any other addicting
substance, without suffering the intense and painful signs and
symptoms of withdrawal.
[0068] The present invention provides accelerated detoxification
methods for the treatment of a substance abuse-related condition in
a subject. In another embodiment, present invention provides
accelerated detoxification methods for the treatment of drug,
alcohol or behavioral addiction.
[0069] Thus, the present invention includes methods of treating or
preventing an addiction, comprising providing one or more opioid
agonist, opioid antagonist or combination thereof to a subject
having an addiction or at risk for developing an addiction. In
various embodiments, the subject is addicted to an addictive agent
or behavior, including, but not limited to, any of the addictive
agents and behaviors described herein. The subject may be
physically or physiologically dependent on the substance or
behavior; the subject may be psychologically dependent; or the
subject may be both physically and psychologically dependent. The
subject may be addicted to one or more than one addictive agent or
behavior.
[0070] As used herein, unless the context makes clear otherwise,
"treat," and similar word such as "treatment," "treating" etc., is
an approach for obtaining beneficial or desired results, including
and preferably clinical results. Treatment can involve optionally
either the reducing or amelioration of a disease or condition,
(e.g., addiction, relapse use, withdrawal), or the delaying of the
progression of the disease or condition (e.g., addiction relapse
use, withdrawal). The subject may be any animal, including a
mammal, and, particularly, a human.
[0071] As used herein, unless the context makes clear otherwise,
"prevent," and similar word such as "prevention," "preventing"
etc., is an approach for preventing the onset or recurrence of a
disease or condition, (e.g., addiction, relapse use, withdrawal) or
preventing the occurrence or recurrence of the symptoms of a
disease or condition, or optionally an approach for delaying the
onset or recurrence of a disease or condition or delaying the
occurrence or recurrence of the symptoms of a disease or condition.
Preventing also includes inhibiting the onset or recurrence of a
disease or condition, or one or more symptoms thereof, and reducing
the likelihood of onset or recurrence of a disease or condition, or
one or more symptoms thereof.
[0072] Generally, a subject is provided with an effective amount of
an opioid agonist, opioid antagonist or combination thereof. As
used herein, an "effective amount" or a "therapeutically effective
amount" of a substance, e.g., an opioid agonist, opioid antagonist
or combination thereof, is that amount sufficient to affect a
desired biological or psychological effect, such as beneficial
results, including clinical results. For example, in the context of
treating addiction using the methods of the present invention, an
effective amount of an opioid agonist, opioid antagonist or
combination thereof is that amount sufficient to cause the subject
to reduce or discontinue use of an addictive agent.
[0073] The terms "substance abuse," "substance-dependence,"
"substance addiction," "drug abuse," "drug dependence," and "drug
addiction," as used herein, may be used interchangeably and refer
to the overindulgence in and dependence on an opiate, a stimulant,
a depressant, and/or other chemical substance, leading to effects
or conditions that are detrimental to the user's physical or mental
health, and/or the welfare of others. Similarly, a substance abuse,
dependence, or addiction-related condition may include, without
limitation, any physical, mental, physiological, pathological,
psychological, psychiatric, and/or clinical conditions related to
the use or abstinence from use of a chemical substance, including
any withdrawal syndrome resulting from discontinuation of use of
substances, such as, opioids or opiates, either natural or
synthetic,
[0074] In one aspect of the invention, the subject is first
determined or diagnosed to have an addiction, or to be at risk of
developing an addiction, by diagnostic testing, observation or
analysis by a medical care provider. An effective amount of an
opioid antagonist, or an effective amount of an opioid antagonist
and one additional therapeutic agent, are then provided to the
subject for treatment or prevention of the addiction. In another
aspect of the invention, the subject is first determined or
diagnosed to have an addiction, or to be at risk of developing an
addiction, by diagnostic testing, observation or analysis by a
medical care provider, but the subject has not been diagnosed or
determined to have diabetes or other insulin disorder. An effective
amount of an opioid antagonist, or an effective amount of an opioid
antagonist and one additional therapeutic agent, are then provided
to the subject for treatment or prevention of the addiction. The
dosage of the opioid antagonist, or the opioid antagonist and the
one additional therapeutic agent, may be specifically determined by
the medical practitioner for treatment or prevention of the
addiction rather than for any other disorder or disease.
[0075] Typical opioid withdrawal syndrome may include, without
limitation, sweating, restlessness, bone and/or joint aches, muscle
spasms/twitching, runny nose or tearing, gastrointestinal
conditions (e.g., without limitation, stomach cramps, nausea,
vomiting, loose stool, and diarrhea), tremor, yawning, anxiety, and
gooseflesh skin. As used herein, the term "substance" may include
any natural, synthetic, opiate, opioid, or narcotic compounds or
compositions (including, without limitation, opioid, opioid
derivatives, opioid agonists, and opioid antagonists). Examples of
such substances include, without limitation, opium, morphine,
heroin, pethidine, methadone, buprenorphine, butorphanol, codeine,
fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine,
oxycodone, pentazocine, propoxyphene, and tramadol.
[0076] As used herein, the phrase "treatment of a substance
abuse-related condition" includes efforts, actions, conducts,
and/or procedures to ameliorate, reduce, minimize, eliminate, or
prevent any physical, mental, physiological, pathological,
psychological, psychiatric, and/or clinical conditions or
impairments related to or resulting from a substance abuse,
addiction, dependence, or the withdrawal therefrom. For example,
without limitation, clinical impairments or symptoms of a substance
abuse-related condition may be ameliorated or minimized by
diminishing any pain or discomfort suffered by the subject; by
inhibiting, reducing, or preventing the development of a substance
abuse-related condition; or by limiting, suspending, terminating,
or otherwise controlling a substance abuse-related condition.
[0077] As used herein, the term "detoxifying amount of an opioid
antagonist" includes an effective amount of an opioid antagonist,
which may substantially saturate, bind to, or block an effective
number of the opioid receptors in a subject. The terms
"substantially saturate" and "substantially block" an effective
number of opioid receptors include about 75%, about 80%, about 85%,
about 90%, about 95%, or higher, saturation or blockage of the
opioid receptors in a subject.
[0078] In one aspect, a detoxifying amount comprises up to about
2000 micrograms of naloxone, which may be given, for example,
intravenously or intramuscularly, to a subject over a period of
time, such as, within 4-6 hours. Such a detoxifying amount of
naloxone may be followed by about 0.5 mg to about 10 mg bolus
administration of an antagonist such as naltrexone, or about 1 mg
to about 8 mg, or about 2 mg to about 6 mg, or about 3 mg to about
5 mg, or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg 8 mg, 9 mg
or 10 mg of an antagonist. Not wishing to be bound by any
particular theory, it is currently thought that providing a bolus
administration of an opiate antagonist provides antagonist support
in the administration of an implant of an opiate antagonist, and
may be additional support for the detoxifying amount of antagonist
provided.
[0079] The treatment method days, up to but not including the
summit day wherein a detoxifying amount of an opiate antagonist is
provided, may be about 1 to about 15 days, or about 2 to about 8
days. On a summit day, a detoxifying amount such as 2,000 ug of an
opiate antagonist such as naltrexone or naloxone may be
administered intravenously, and optionally followed by a bolus
administration of an opiate antagonist. The summit day may be
followed by continuous administration of an opiate antagonist, such
as by providing a sustained release delivery form of an opiate
antagonist, such as naltrexone.
[0080] For example, an 8 day treatment method may be appropriate
for subjects dependent on methadone, buprenorphine, suboxone, or
other long-acting opiates because of the long half-life of those
drugs and the severity of the withdrawal symptoms if the
detoxifying treatment is performed too rapidly. In one aspect, the
subject may use as small amounts of opioids (e.g., tramadol) as
possible and use as large amounts of micro-dose opioid antagonists
(e.g., naltrexone) as possible, in part to control withdrawal
symptoms, during the treatment period up to the summit day.
[0081] To aid in preventing relapse following the detoxifying
treatment, an opioid antagonist (e.g., naltrexone or Vivitrol) may
be administered to the subject for an extended period of time, such
as, for about 1 to about 24 months, or for about 12 months. The
opioid antagonist may be given to the subject using any suitable
method, such as, but not limited to, orally, I.M. (intramuscular
injection) or in an implant form. In one aspect, the opioid
antagonist, such as, naltrexone, may be given to the subject in the
form of a controlled/sustained release pharmaceutical composition.
For example, a sustained release pellet containing naltrexone may
be implanted under the subject's skin, such as, without limitation,
in the fatty tissue of the lower abdomen. The controlled release
pharmaceutical composition may release an effective amount of the
opioid antagonists (e.g., naltrexone) over a period of more than
about 6 to about 8 weeks or more than about 8 to about 10 weeks, up
to about 12 or about 24 months. Controlled release pharmaceutical
compositions comprising opioid antagonist (e.g., naltrexone) and
methods for delivering an effective amount of opioid antagonist are
known in the art.
[0082] The compositions of the present invention may be
administered to a subject independently, or together with other
pharmaceutical compositions. It may also be administered to a
subject together with food or a beverage.
[0083] A pharmaceutical composition of the present invention may be
administered to a subject by known procedures, including, without
limitation, oral administration, parenteral administration,
transdermal administration, nasal administration, and by way of
catheter. For example, the pharmaceutical composition may be
administered orally, parenterally, by epifascial, intracapsular,
intracranial, intracutaneous, intrathecal, intranasal,
intramuscular, intraorbital, intraperitoneal, intraspinal,
intrasternal, intravascular, intravenous, parenchymatous,
subcutaneous, or sublingual administration. The pharmaceutical
composition may be provided in an amount effective to treat a
pathological or psychiatric condition in a subject to whom the
composition is administered. As used herein., the phrase "effective
to treat a disorder" means effective to eliminate, ameliorate,
reduce, minimize, or prevent the clinical impairment or symptoms
associated with the disorder.
[0084] For oral administration, the pharmaceutical composition of
the present invention may be presented as capsules, tablets,
powders, granules, or as a suspension, among others. The
formulation may have conventional additives, such as, but not
limited to, lactose, mannitol, corn starch, or potato starch. The
formulation also may be presented with binders, such as,
crystalline cellulose, cellulose derivatives, acacia, corn starch,
and gelatins, among others. Additionally, the formulation may be
presented with disintegrators, such as, but not limited to, corn
starch, potato starch, and sodium carboxymethylcellulose. The
formulation also may be presented with dibasic calcium phosphate
anhydrous or sodium starch glycolate. Moreover, the formulation may
be presented with lubricants, such as talc and magnesium
stearate.
[0085] For parenteral administration (i.e., administration by
injection through a route other than the alimentary canal), the
pharmaceutical composition of the present invention may be combined
with a sterile aqueous solution that may be isotonic with the blood
of the subject. Such a formulation may be prepared by dissolving
the pharmaceutical composition of the present invention in water
containing physiologically-compatible substances, such as sodium
chloride, glycine, and the like, and having a buffered pH
compatible with physiological conditions, so as to produce an
aqueous solution, then rendering said solution sterile. The
formulation may be presented in unit or multi-dose containers, such
as sealed ampoules or vials. The formulation may be delivered by
any mode of injection, including, without limitation, epifascial,
intracapsular, intracranial, intracutaneous, intrathecal,
intramuscular, intraorbital, intraperitoneal, intraspinal,
intrasternal, intravascular, intravenous, parenchymatous,
subcutaneous, and sublingual.
[0086] For transdermal administration, the pharmaceutical
composition of the present invention may be combined with skin
penetration enhancers, such as propylene glycol, polyethylene
glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, and
the like, which increase the permeability of the skin to the
pharmaceutical composition, and permit the pharmaceutical
composition to penetrate through the skin and into the bloodstream.
The pharmaceutical composition of the present invention may be
further combined with a polymeric substance, such as
ethylcellulose, methylcellulose, hydroxypropyl cellulose,
ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to
provide the composition in gel form, which may be dissolved in a
solvent, such as methylene chloride, evaporated to the desired
viscosity, and then applied to backing material to provide a
patch.
[0087] The pharmaceutical composition of the present invention may
comprise a pharmacological effective amount of a compound and a
pharmaceutically-acceptable carrier. The
pharmaceutically-acceptable carrier may be "acceptable" in the
sense of being compatible with the other ingredients of the
composition, and not deleterious to the recipient thereof. The
pharmaceutically-acceptable carrier employed herein may be selected
from various organic or inorganic materials that are used as
materials for pharmaceutical formulations, and which may be
incorporated as analgesic agents, buffers, binders, disintegrants,
diluents, emulsifiers, excipients, extenders, glidants,
solubilizers, stabilizers, suspending agents, tonicity agents,
vehicles, and viscosity-increasing agents. If necessary,
pharmaceutical additives, such as antioxidants, aromatics,
colorants, flavor-improving agents, preservatives, and sweeteners,
may also be added. Examples of acceptable pharmaceutical carriers
include carboxymethyl cellulose, crystalline cellulose, glycerin,
gum arabic, lactose, magnesium stearate, methyl cellulose, powders,
saline, sodium alginate, sucrose, starch, talc, and water, among
others.
[0088] In one embodiment, the auricular or peri-auricular
electro-acupuncture or neurostimulation device comprises: [0089]
(a) a stimulator comprising (i) a generator for generating
electrical stimulation pulses with defined stimulation parameters,
(ii) a voltage supply for supplying the generator with electrical
energy and (iii) a control device for generating stimulation pulses
from the generator having a defined current voltage or current
amplitude, a defined duration, a defined repetition frequency and a
defined duty cycle; [0090] (b) at least one therapy electrode
connected to the stimulator for providing stimulation pulses to an
area to be stimulated; and [0091] (c) at least one reference
electrode connected to the stimulator for providing a ground
connection for the stimulator [0092] (d) wherein the, at least one
therapy electrode comprises an array of at least two (2) needle
electrodes for insertion into the skin surface of an area to be
stimulated; [0093] (e) wherein the needle electrode array is
designed for auricular peripheral or cranial nerve field
stimulation.
[0094] A stimulation device, wherein the electrical signal
generator is configured to generate electrical stimulation pulses
having a repetition frequency of 0.5 to 300 Hz and a duty cycle of
5-100%, preferably 98-100% and wherein the stimulation pulses are
generated at a constant current amplitude.
[0095] A stimulation device, wherein the electrical signal
generator is configured to generate electrical stimulation pulses
having a frequency modulating from 0 to 300 Hz. A stimulation
device, wherein the electrical signal generator is configured to
generate electrical stimulation pulses having a frequency
modulating from 1 Hz, 3 Hz, 7 Hz, 10 Hz, repeating. A stimulation
device, wherein the voltage output to the therapy electrodes is in
the range of about 0.001 volts to 6 volts.
[0096] A stimulation device, wherein the electronic aspects of the
electrical stimulation device are implemented by means of an
analogue circuit, a digital circuit or a computer arrangement with
a processor instructed by a suitable computer program, or any
combination thereof. A stimulation device, wherein the stimulator
further comprises a program for performing stimulation wherein the
program is resident in a memory and executed by a microprocessor to
control the stimulator.
[0097] A stimulation device, wherein the control device is coupled
to operating elements for changing the stimulation parameters. A
stimulation device, wherein the control device is coupled to
operating elements comprising controls for the ability to adjust
the voltage output to the, therapy electrodes by manipulation of
one or more parameters selected from the group consisting of pulse
frequency, pulse width, provision of sequential pulses, output of
more than one pulse at a time and combinations thereof.
[0098] A stimulation device, further comprising a memory for
recording the stimulation parameters as a function of time.
[0099] A stimulation device, wherein the control device comprises
electrically erasable programmable read-only memory (EEPROM)
configured to provide electrical pulses for at least 2 hours,
follow by at least 30 seconds of a low power delay cycle with no
pulse output.
[0100] Aspects of the present disclosure are directed toward
auricular nerve stimulation at terminals in one and/or both ear
lobes, and based on events that are simultaneous, synchronous, in
alternating sequences and/or with different off times, and to
providing systems, apparatuses, and methods for application of
stimulation for reproducible stimulation of the auricular nerve or
nerves with minimal operator dependence.
[0101] Device, systems, methods and kits can be useful for
auricular stimulation. One such device relates to auricular
stimulation. The device includes one or two earpieces having an
electrode arrangement configured and arranged to deliver a series
of electrical stimulation signals to one or two auricular
locations.
[0102] Certain embodiments of the present disclosure are directed
toward an auricular stimulation device that has an earpiece having
an electrode and configured and arranged to deliver a series of
electrical stimulation signals to a first auricular location of a
particular individual based upon anatomical measurements from the
particular individual. A pulse-generator circuit is configured and
arranged to generate the series of electrical stimulation signals,
and to deliver the electrical stimulation signals to the
electrode.
[0103] Various embodiments of the present disclosure are directed
toward a method of auricular stimulation. A stimulation location is
determined from anatomic points of an ear of a subject. An
earpiece, having a stimulation electrode, is positioned so as to
locate the stimulation electrode in a location corresponding to the
stimulation location. A series of electrical stimulation signals
are delivered to the stimulation electrode according to a
stimulation profile.
Additional Embodiments
[0104] The methods of the present invention make use of an
electrical stimulation device including a stimulator described for
treating symptoms of drug withdrawal, specifically withdrawal from
opioids.
[0105] A protocol has been described to make use of device along
with medications designed to promote comfort for an approximately
5-day period with the goal to get onto opioid antagonist therapy
with a long acting naltrexone product. Long acting naltrexone
currently comes in the form of a monthly depot injection, Vivitrol,
and various naltrexone implants.
[0106] Published study describes 85% of opioid withdrawal symptoms
being controlled within 30 minutes. Residual symptoms are
controlled using comfort medications described in protocol.
(Miranda A, Babygirija R. Neurostimulation with IBStim attenuates
amygdala neurons and prevents post-inflammatory visceral and
somatic hyperalgesia in rats. World Congress of pediatric
gastroenterology, hepatology and nutrition).
[0107] Mechanism of action of device is most likely from autonomic
regulation from stimulating the Vagus Nerve promoting
Parasympathetic activity. Imaging study in rats shows 65% reduction
in neuronal firing of the Amygdala, the area of the brain which
controls emotional tone which includes fear, terror, and anxiety.
(Journal of Addiction Medicine. Neuromodulation with BRIDGE is
Associated with Reduction in Signs and Symptoms of Opioid
Withdrawal-A Retrospective, Multisite Study).
[0108] Other possible mechanisms of action include disruption of
ascending and descending pain tracks of the dorsal column,
stimulation of Trigeminal nerve causing release of pain modulating
neurochemicals of endorphin from para-aqueductal grey and serotonin
from raphe nucleus.
[0109] Comfort medication are utilized within this period of
detoxification because of presence of residual symptoms. Possible
explanation of incomplete resolution of withdrawal symptoms can be
explained by nerve attenuation during this period. Nerve
attenuation can be described as the reduction of the amplitude of a
signal, electric current, or action potential of a nerve.
[0110] In one embodiment, the present invention includes a method
of treating or preventing an addiction, comprising determining that
a subject has or is at risk of developing an addiction, and
providing to the subject one or more non-narcotic detox medications
used in combination with one or more auricular or peri-auricular
electro-acupuncture or neurostimulation device for a time effective
for the treatment or prevention of the addiction.
[0111] In a related embodiment, the present invention provides a
method of treating or preventing an addiction, comprising providing
to a subject having an addiction one or more non-narcotic detox
medications used in combination with one or more auricular or
peri-auricular electro-acupuncture or neurostimulation device and
an additional therapeutic agent, wherein each of the one or more
non-narcotic detox medications and the additional therapeutic agent
contribute to the effective treatment or prevention of the
addiction.
[0112] In one embodiment, the invention providers for a method of
treating or preventing an addiction, comprising providing to a
subject having an addiction one or more non-narcotic detox
medications used in combination with one or more auricular or
peri-auricular electro-acupuncture or neurostimulation device
wherein the left side of the body is implanted first to reduce
chance of any cardiac effects. Without wishing to be bound by
theory, it is believed that the right side has some projections to
the heart and can cause feinting. In another embodiment, the left
side of the body is implanted only without implantation on the
right side to reduce chance of any cardiac effects. In another
embodiment, the right side can be used if left sided cannot be
done.
[0113] In one embodiment, the invention providers for a method of
treating or preventing an addiction, comprising right sided vagus
nerve stimulation. The vagus nerve, also called X cranial nerve or
10th cranial nerve, is the longest and most complex of the cranial
nerves. The vagus nerve runs from the brain through the face and
thorax to the abdomen. It is a mixed nerve that contains
parasympathetic fibres. One or more auricular or peri-auricular
electro-acupuncture or neurostimulation devices can be used to
stimulate the vagus nerve on and around the neck and ear.
[0114] In one embodiment, the invention providers for a method of
treating or preventing an addiction, comprising bilateral
implantation using two devices that are identically pre-programmed
for an amount of time alternating on/off stimulation on each ear
for the period of the detoxification. This is to reduce nerve
attenuation and need for complicated comfort medication
regimen.
[0115] In one embodiment, the invention providers for a method of
treating or preventing an addiction, comprising using the left ear
first for stimulation before the right. In one embodiment, the left
ear is the preferred site as the right sided auricular branches of
the vagus nerve innervates the sinoatrial node of the heart and
influences the heart rate. R-VNS seems to be an effective and
alternative therapy in selected patients responding to L-VNS where
a left-sided reimplantation is not possible. (Epilepsy Res. 2008
December; 82(2-3):232-4. doi: 10.1016/j.eplepsyres.2008.08.003.
Epub 2008 Sep. 18.)
[0116] Nerve Attenuation
[0117] Because of possible nerve attenuation during this period, an
approach has been described to take advantage of bilateral
auricular and facial branches of Cranial Nerves.
[0118] Cardiac slowing in response to a standard electrical
stimulus applied to the vagus (1-2 Hz for 10 s) was potentiated
after a 2-min high frequency stimulation (10 Hz). This potentiation
of cardiac vagal action was abolished after a 1-hour period of
repetitive vagal stimulation. (Cardiac vagal effects in the toad
are attenuated by repetitive vagal stimulation. Neuropeptides. 1993
September; 25(3):193-8.)
[0119] Bilateral Approach
[0120] In one embodiment, the protocol requires two pre-programmed
devices implanted bilaterally. The first device would be implanted
and be programmed with alternating times of stimulation. Once the
first device is programmed to stop stimulation, to prevent nerve
attenuation, a second device would be installed in the opposite
ear. The second device would take over stimulation for the same
period while the first device is off.
[0121] Since nerve attenuation can be seen between 1-6 hours of
placement of the device, it is suggested that both devices be
programmed with identical alternating stimulations for 1-6 hours.
In one embodiment, a schedule with 2-3 hours on/off schedule is
used.
[0122] For example, a person presents in moderate to severe opioid
withdrawal. Device #1 is installed, and patient is either
supervised in the clinic for the next 2 hours or asked to come back
within 2 hours to prepare for installation of device #2. It is
important to implant device #2 when device #1 is programmed to be
off. After 2 hours the patient presents again to the clinic and
device #2 is installed in the opposite ear. Device #1 will not be
taken off. Both devices will be worn for the total of 120 hours (5
days).
[0123] In one embodiment, both devices are identically
pre-programmed, in this example, for 2 hours of alternating
electrical stimulation. This approach can minimize nerve
attenuation and use of comfort medications. This can then reduce
the total drug amounts needed for treatment.
Example Devices that can be used in the Present Methods
[0124] The present invention relates to methods and systems for
treatment of addiction using electrode placement for auricular
peripheral nerve field stimulation (PNFS) using a method of
anatomical visualization and percutaneous implantation of an
electrode complex(s) designed as a needle array.
[0125] In one embodiment, the invention providers for a single use
device that is physician applied for ambulatory, continuous, home
based therapy. In one embodiment, the stimulator is percutaneously
implanted into the cranial and/or peripheral nerves and
corresponding neural vascular bundles of the auricular and
periauricular areas as ascertained by the method of evaluating and
implanting of the electrode/needle array provided in the present
invention. This includes transillumination of the auricular and
periauricular tissues and surrounding neurovascular anatomy. The
auricular peripheral nerve stimulator system allows for continuous,
intermittent neural stimulation.
[0126] In one embodiment, the auricular peripheral nerve stimulator
system is a battery-operated, single-use device that has a
preprogrammed frequency, pulse and duration for the stimulation of
selected cranial and/or peripheral nerves and corresponding neural
vascular bundles of auricular and periauricular areas. In one
embodiment, the device power supply connects via three or more
electrical conduit wires, sheathed in electrically insulating
material, to one or more therapy electrode arrays comprised of
multiple needles each and one reference electrode.
[0127] In another embodiment, the device comprises two or more
needle arrays comprised of multiple needles each. In another
embodiment, the device comprises three or more needle arrays
comprised of multiple needles each. In another embodiment, the
device comprises four or more needle arrays comprised of multiple
needles each. In another embodiment, the needle arrays are
comprised of two or more needles each. In another embodiment, the
needle arrays are comprised of three or more needles each. In
another embodiment, the needle arrays are comprised of four or more
needles each. In another embodiment, the needle arrays are
comprised of five or more needles each. In another embodiment, the
needle arrays are comprised of six or more needles each.
[0128] Turning to the drawings, FIGS. 1A-1B depict an electrical
stimulation device 10 for, in particular, an electrical acupuncture
therapy in the region of an ear 12 of a human being 14. The
stimulation device lo includes a stimulator 18 containing a
generator 20 for generating stimulation pulses with defined
stimulation parameters, i.e. a defined voltage or a defined
current, a defined duration, a defined repetition frequency and a
defined duty cycle etc. In one embodiment, the electrical
stimulation device 10 comprises an electrical signal generator 20
configured to generate electrical stimulation pulses having a
repetition frequency of 0.5 to 100 Hz, preferably 1-10 Hz, and a
duty cycle of 10 to 90%, preferably 40-60%. In one embodiment, the
stimulation pulses are generated at a constant current
amplitude.
[0129] With particular reference to FIG. 1B, electronic aspects of
the electrical stimulation device 10 may be implemented by means of
an analogue circuit, a digital circuit or a computer arrangement
with a processor instructed by a suitable computer program, or any
combination thereof. In one embodiment, a program 22 for performing
stimulation is resident in memory 24 and executed by a
microprocessor 26 to control the stimulator 18. The memory 24 may
be implemented as several memory units of different types (RAM,
ROM, etc.). The memory 24 stores instructions of a program 22 to
allow a microprocessor 26 to perform one or more functions.
Optionally, memory 24 stores a number of detected parameter values
as obtained from detection devices 28, such as incorporated in an
electrode needle array 30. The memory 24 may be any suitable memory
24 for storing a predetermined function such as a computer readable
memory 24. The predetermined function may be a mathematical
function or correlation. Suitable functions may be functions that
are suitable for determining whether a determined parameter value
is equal to, greater than or smaller than a predetermined threshold
value. Based on his knowledge the skilled person will be able to
determine suitable functions on the basis of which a response is
required as a function of the determined parameter values. For
example, the function may relate the absence of certain parameter
values below a certain threshold value to a certain time frame.
Such a function may be determined to detect the absence of
breathing during a certain time period e.g. 1 second and longer, 2
seconds and longer or 5 seconds and longer.
[0130] Based on the program 22 as stored in the memory 24, the
microprocessor 26 is able to process the number of detected
parameter values as obtained from the detection device in said
function. For this, the detected parameter values are loaded into
the microprocessor 26 either directly from the detection devices 28
or alternatively from the memory 24 into which the detected
parameter values were previously loaded. The function is loaded in
the microprocessor 26 from the memory 24 or in an alternative
embodiment the predetermined function may be embedded in said
microprocessor 26. In the latter embodiment at least one memory 24
is (partially) integrated in the microprocessor 26. In one
embodiment, the memory 24 records the stimulation parameters as a
function of time as data 25 to enable the performance of a quality
control check or check of the proper operation by a remote control
device 27 that is periodically or permanently in communication with
the stimulation device 10 via wireless or wired connection 29.
[0131] The detection device 28 may be any suitable device for
detecting a number of parameter values. In the present
specification, a "number" shall mean one or more unless explicitly
stated otherwise. Parameters suitable for determining whether a
subject is in need of resuscitation include but are not limited to
parameters corresponding to muscle activity, parameters
corresponding to breathing, or parameters corresponding to cerebral
activity, such as electrical activity of neural cells including
brain cells, or electrical activity recorded from the ear or any
other suitable point on the body of a human being 14. Other sensors
may be applied as well, like a sensor to measure body temperature,
a sensor to measure pressure, and a sound sensor, like a
microphone.
[0132] A power supply 32 is provided in order to supply the
components of the stimulator 18 with electrical energy. In one
embodiment, the power supply 32 is formed by a suitable battery 34
or an accumulator. The electrical pulses generated in the generator
20 of the stimulator 18 are delivered via at least one needle
electrode array 30 comprising at least two therapy electrode arrays
36 and at least one ground or reference electrode 38.
[0133] Each therapy electrode 36 has two or more needle electrodes
40, which in an exemplary embodiment is four (4) in number. In one
embodiment, the number of therapy electrodes 36 is selected from
the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. In
another embodiment, the number of needle electrodes 40 per therapy
electrode 36 is selected from the group consisting of 2, 3, 4, 5,
6, 7, 8, 9, 10, or more.
[0134] In one embodiment, the number of needle electrodes 40 per
therapy electrode 36 is 2-10. In one embodiment, the number of
needle electrodes 40 per therapy electrode 36 is 3-9. In one
embodiment, the number of needle electrodes 40 per therapy
electrode 36 is 4-8. As seen in FIG. 1B, the array may include one
or more therapy electrode 36' and 36'', alone or in combination,
with five (5) and six (6) needle electrodes 40, respectively.
[0135] The present invention has shown that the use of therapy
electrode 36 having a plurality of two or more needle electrodes
40--and preferably 3 or more and more preferably 4 or
more--provides for the unexpected result of a synergistic filed
effect and not merely an additive electrical stimulation for pain
reduction.
[0136] Each reference electrode 38 includes at least at least one
needle electrode 40. The therapy electrodes 36 and reference
electrode 38 are inserted into the skin surface in the area to be
stimulated. The reference electrode 38 provides a ground connection
for electronic circuit located within the stimulator 18.
[0137] In one embodiment, the needle electrodes are made of an
electrically conductive material, in particular a metal such as
titanium, stainless steel or the like. In addition to metals,
conductive synthetics are also conceivable for the production of
the needle electrodes.
[0138] In one embodiment, the at least two needle electrodes 40 of
the therapy electrode 36 are arranged in a common electrode housing
42 with a detection device 28 and connected to the stimulator 18 by
an appropriate line 44. A circuit board 45 (FIG. 1B) on which the
one or more needle electrodes 40 are mounted is arranged in the
common electrode housing 42. The therapy electrodes 36 can, for
instance, be simply connected to the circuit board 45 by a
conductive adhesive. The line 44 is likewise connected to the
circuit board 45, either by a solder joint or by a screw
connection, the conductive tracks of the circuit board 45
safeguarding the electrical connection to the therapy electrodes
36. The arrangement of each therapy electrode 36 in a common
electrode housing 42 provides for a defined distance between the
individual needle electrodes 40. The line 44 for connecting the
therapy electrodes 36 to the stimulator 18 can be fixedly, i.e.
inseparably, or even detachably configured. Each line 44 can be
fixedly connected respectively to the corresponding therapy
electrode 36 or reference electrode 38. Each line 44 can also be
fixedly connected to the stimulator 18. In the illustrative
embodiment, each line 44 terminates at a plug 46 that is physically
and electrically connected to a socket 48 mounted on an electronic
housing 50 that contains the stimulator 18.
[0139] In order to attach the electronic housing 50 to the skin
surface, a fastening element 54 (FIG. 1B), such as an adhesive
element, may be provided. Besides the adhesive element, other
fastening methods, e.g. via magnets, elastic bands or the like can
be used. The fastening element can be integrated in the electrode
housing. For example, the electronic housing 50 can adhesively
mount behind the ear 12 of the human being 14 (FIG. 1A). The
electronic housing 50, which may be made of a synthetic material
and is preferably designed to be water-proof. The components
depicted in FIG. 1A can be arranged in a preferably sterile package
(not illustrated) so as to prevent any contamination of the needle
electrode array 30.
[0140] In another embodiment, the auricular peripheral nerve
stimulator system is a battery-operated, single-use device that has
a pre-programmed frequency, pulse and duration for the stimulation
of selected cranial and/or peripheral nerves and corresponding
neural vascular bundles of auricular and periauricular areas.
[0141] In another embodiment, the auricular peripheral nerve
stimulator is a single use device that is physician applied for
ambulatory, continuous, home based therapy. It is to be
percutaneously implanted into the cranial and/or peripheral nerves
and corresponding neural vascular bundles of the auricular and
periauricular areas as ascertained by the disclosed method of
evaluating and implanting of the electrode/needle array. This
includes transillumination of the auricular and periauricular
tissues and surrounding neurovascular anatomy. The auricular
peripheral nerve stimulator system allows for continuous,
intermittent neural stimulation for up to five days.
[0142] In another embodiment, electrode/needle array implantation
into the skin of the ear allows for direct access to branches of
cranial nerves V, VII, IX, and X as well as branches of the
occipital nerves. Direct access to the arterial branches of the
head and neck are accessible and reduction of sympathetic
stimulation results in an increase of vascular flow rate, reduction
of vascular resistance and increase of perfusion. The arterial
branches of the superficial temporal artery and the posterior
auricular artery form a rich interconnecting complex network the
terminal branches of which anastomose throughout the ear.
[0143] In another embodiment, the auricular peripheral nerve
stimulator alters production and utilization of serotonin via vagal
stimulation, and meningovascular dilation secondary to decreased
sympathetic (or increased parasympathetic) tone.
[0144] The actual location and determination of needle placement
(called points) is based upon tradition and theory of acupuncture.
While the ascribed "points" may vary, depending upon the type of
acupuncture to which one prescribes, the rationale and needle
placement varies little and the theory is the same.
[0145] The addition of electrical stimulation to the individual,
non-connected needles does not alter the rationale and the location
of application is still based upon the original theory. The
addition of electricity, while considered an enhancement, still
falls within the realm of auricular acupuncture.
[0146] The present invention provides methods not based upon
acupuncture technique or "points" but rather peripheral nerve field
stimulation, anatomical location of cranial nerves, peripheral
nerves, arterial branches and/or neurovascular bundles, and energy
transfer based upon accepted laws of energy transfer in human
tissue. Peripheral nerve field stimulation is an accepted procedure
for the affecting of targeted nerves to alter pain transmission on
a local (peripheral) and CNS (central nervous system) level. PNFS
is commonly used in the occipital nerves (branches of the cervical
nerves) for headache control, and the femoral nerve of the leg for
control of phantom limb pain, stump pain, and other types of
peripheral pain. The PNFS technique is based upon neuro-anatomy,
blood vessel anatomy, proximity of the electrodes to the actual
nerves being stimulated, and verification of electrode
proximity.
[0147] Without wishing to be bound by theory, the method of
auricular application of PNFS relies on the fact that located
within the ear are cranial nerves V, VII, IX, X which anastomose
(connect) directly into the brain and branches of the greater and
lesser occipital nerves anastomosing directly into the cervical
spine. There are distinct areas of the auricle on both the dorsal
and ventral aspect which carry a predominance/concentration of the
cranial nerves, peripheral nerves, arterial branches, and
neurovascular bundles.
[0148] Branches of the superior temporal artery and the posterior
auricular artery are found within the external ear, entering from
the anterior (ventral) and posterior (dorsal) aspect of the ear.
These arteries converge in the lobe, branching eventually into the
cellular level forming a complex, interconnecting network branching
according to Mandelbrot's set.
[0149] For a stimulation therapy in the case of certain disorders
or illnesses and, e.g., for achieving a homogenous sensation at the
entire ear it is advantageous to continuously change the polarity
of the therapeutic currents. For this, a configuration of the
inventive device is provided which is characterized in that during
a current flow of the therapeutic currents fed to the individual
stimulation electrodes, these stimulation electrodes, at the time
considered in each case, have polarities which differ from each
other with regard to a reference potential point which is connected
with the therapeutic current circuits. This configuration results
also in an at least partial relief of a reference electrode
connected to the reference potential point from the therapeutic
currents flowing through the stimulation electrodes. This effect
applies to an even greater extent to a refinement, which is
characterized in that the therapeutic currents, which are fed to
the individual stimulation electrodes which have polarities which
differ from each other at the respectively considered time,
compensate each other at the respectively considered time so that
no therapeutic current flows through a reference electrode. In this
manner, a reference electrode can be eliminated. It is further
beneficial if it is provided that the control circuit--which is
provided in the micro-computer circuit and which feeds a control
signal to the amplifiers provided in the output channels, which
said control signal, in a cyclical succession, forms time intervals
in which a current flow to the stimulation electrodes takes place
and time intervals in which the output channels are inactive,
wherein in each case one current flow time interval and one
inactive time interval together form one stimulation cycle, and
wherein in the current flow time intervals, a therapeutic current
flows in the form of a packet of successive pulses or in the form
of a single pulse--causes a polarity reversal at each current flow
time interval. It is preferably provided in this connection that
the polarity reversal is caused within the current flow time
intervals. This is often considered as being therapeutically
beneficial.
[0150] As already mentioned above, it is advantageous for certain
stimulation therapies, e.g. pain therapies for chronic disorders,
to start with low values at the beginning of the treatment and to
slowly increase the intensity of the stimulation to the full
intended extent. For this, an embodiment of the device according to
the invention is provided which is characterized in that the
control circuit--which is provided in the micro-computer circuit
and which feeds a control signal to the amplifiers provided in the
output channels, which said signal, in a cyclical succession, forms
time intervals in which a current flow to the stimulation
electrodes takes place and time intervals in which the output
channels are inactive, wherein in each case one current flow time
interval and one inactive time interval together form one
stimulation cycle--at the beginning of a stimulation cycle sequence
formed by a multiplicity of successive stimulation cycles,
continuously increases during a plurality of successive stimulation
cycles from in each case one stimulation cycle to the next
following stimulation cycle the intensity of the therapeutic
current fed to a respectively considered stimulation electrode, the
intensity being considered as average over the respective current
flow time interval, and subsequently maintains during a
multiplicity of successive stimulation cycles within their current
flow time intervals the previously achieved level of intensity of
the therapeutic currents. Thereby, the sensation of the stimulation
as well as the effect of the treatment can be further improved if
it is provided that at the end of the stimulation cycle sequence,
the control circuit feeds a control signal to the amplifiers
provided in the output channels, which said control signal
continuously decreases from in each case one stimulation cycle to
the next following stimulation cycle the intensity of the
therapeutic current fed to a respectively considered stimulation
electrode, the intensity being considered as average over the
respective current flow time interval.
[0151] With regard to the energy supply of the device according to
the invention, an embodiment is preferred which is characterized in
that for supplying the amplifiers provided in the output channels,
a voltage transformer with a bipolar output is provided which, for
its part, is supplied by the battery provided in the device. In
this manner, supplying the amplifiers can be carried out with a
battery which is formed from only one cell or few cells and, in a
given space, has a relatively high energy content which enables a
stimulation operation over several days. Another extension of the
treatment duration possible with the device can be achieved by
minimizing the losses occurring in the mentioned voltage
transformer. For this, a refinement of the aforementioned
embodiment provides that in the connection supplying from the
battery to the voltage transformer, a switching device is inserted
which interrupts the supply during the current flow pauses present
in the therapeutic current circuits as well as upon exceedance of a
predefined limit value of the current drawn by the voltage
transformer from the battery. Besides the energy-saving function,
the switching device has the function of protection against
overloading the battery and against exceeding predefined values of
the therapeutic currents.
[0152] Another embodiment which is effective in terms of the best
possible utilization of the energy contained in the supplying
battery is characterized in that for supplying the micro-computer
circuit, the digital-analog converter and potentially provided
measurement signal circuits, a voltage transformer is provided
which has an unipolar output and is connected to the battery,
wherein said voltage transformer is bypassed with a Schottky diode
and is activated only when the battery voltage falls, and delivers
at its output a voltage that corresponds to the battery target
voltage.
[0153] For setting the parameters of the therapeutic currents for
the respective present treatment case, an embodiment of the device
according to the invention is advantageous and preferred which is
characterized in that the device has a wirelessly operating
transmission device which is connected to the micro-computer
circuit and serves, by means of an external control device, for
entering parameters to be stored of the therapeutic currents
provided for the respective treatment. Furthermore, it can
advantageously be provided that the device has a wirelessly
operating transmission device which is connected to the
micro-computer circuit and serves for transmitting stored
parameters of the therapeutic currents provided for the respective
treatment to an external control and monitoring device.
[0154] All publications, patents and patent applications cited
herein, whether supra or infra, are hereby incorporated by
reference in their entirety to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated as incorporated by
reference. It should be appreciated that any patent, publication,
or other disclosure material, in whole or in part, that is said to
be incorporated by reference herein is incorporated herein only to
the extent that the incorporated material does not conflict with
existing definitions, statements, or other disclosure material set
forth in this disclosure. As such, and to the extent necessary, the
disclosure as explicitly set forth herein supersedes any
conflicting material incorporated herein by reference. Any
material, or portion thereof, that is said to be incorporated by
reference herein, but which conflicts with existing definitions,
statements, or other disclosure material set forth herein, will
only be incorporated to the extent that no conflict arises between
that incorporated material and the existing disclosure
material.
[0155] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the content clearly dictates otherwise.
Thus, for example, reference to a "colorant agent" includes two or
more such agents.
[0156] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
a number of methods and materials similar or equivalent to those
described herein can be used in the practice of the present
invention, the preferred materials and methods are described
herein.
[0157] As will be appreciated by one having ordinary skill in the
art, the methods and compositions of the invention substantially
reduce or eliminate the disadvantages and drawbacks associated with
prior art methods and compositions.
[0158] It should be noted that, when employed in the present
disclosure, the terms "comprises," "comprising," and other
derivatives from the root term "comprise" are intended to be
open-ended terms that specify the presence of any stated features,
elements, integers, steps, or components, and are not intended to
preclude the presence or addition of one or more other features,
elements, integers, steps, components, or groups thereof.
[0159] As required, detailed embodiments of the present invention
are disclosed herein; however, it is to be understood that the
disclosed embodiments are merely exemplary of the invention, which
may be embodied in various forms. Therefore, specific structural
and functional details disclosed herein are not to be interpreted
as limiting, but merely as a basis for the claims and as a
representative basis for teaching one skilled in the art to
variously employ the present invention in virtually any
appropriately detailed structure.
[0160] While it is apparent that the illustrative embodiments of
the invention herein disclosed fulfill the objectives stated above,
it will be appreciated that numerous modifications and other
embodiments may be devised by one of ordinary skill in the art.
Accordingly, it will be understood that the appended claims are
intended to cover all such modifications and embodiments, which
come within the spirit and scope of the present invention.
* * * * *